Abstract 1544: All-Trans Retinoic Acid Regulates Adiponectin in vivo and in vitro
Obesity is associated with reduced levels of adiponectin (ADPN), an anti-inflammatory, insulin sensitizing, PPARγ-regulated adipokine. In diabetic patients, PPARγ-activating thiazolidinediones increase ADPN levels, an effect that may underlie these agents’ putative vascular benefits. In contrast, endogenous regulation of ADPN is poorly understood. PPAR responses require retinoid X receptor (RXR) activation by its natural agonist, 9-cis retinoic acid (9-cis RA). In vivo, all-trans RA (atRA) is the major RA isomer, can be converted to 9-cis RA, and is a retinoic acid receptor (RAR) ligand. We hypothesized that RA and its metabolites may regulate ADPN levels. To test this, ob/ob mice on regular chow received daily intraperitoneal injections of atRA (500nM) or vehicle (n=3/group, 3 weeks). Although all mice displayed the similar expected weight gain, plasma ADPN levels were 3.3-fold higher in atRA-treated mice vs. controls (p<0.01, ELISA). Treatment with atRA also improved glucose tolerance (max. glucose 453±55 vs. 807±251 mg/dL, p<0.05). Given these effects, RAR and RXR regulation of ADPN levels was studied in 3T3-L1 mouse pre-adipocyte differentiation assays (7 days) with or without 9-cis/atRA and in the presence or absence of siRNA to all RAR (α/β/γ) and RXR (α/β) isoforms. siRARα/β/γ had no effect on ADPN levels in media of differentiated adipocytes, while siRXRα/β decreased ADPN 10-fold (p<0.05). siRXRα alone decreased ADPN levels 4-fold (p<0.05), while siRXRβ increased ADPN 1.5-fold (p<0.01), suggesting distinct RXRα and -β roles in adipogenesis. During adipogenesis, RXRβ, which suppresses ADPN, is constitutively expressed; RXRβ, which stimulates ADPN secretion, is induced after 24h differentiation. As expected, treatment with 9-cis or atRA at 24h suppressed ADPN mRNA expression (Northern blot) and secretion. In contrast, 9-cis or atRA stimulation later in differentiation (58h) increased ADPN mRNA expression, while only atRA increased protein secretion. These divergent ADPN responses to atRA vs. the RXR ligand 9-cis RA suggest possible RXR-independent mechanisms and/or atRA conversion to other mediators. Together, these data reveal atRA action through RXR as a novel pathway regulating ADPN levels in vivo and in vitro.